The estimated global burden of suicide is about one million deaths per year. Being one of the leading causes of death, suicide receives increasing attention worldwide, with many countries (including USA) developing national strategies for prevention. Up to 90% of adults who commit suicide have at least one psychiatric diagnosis (e.g., major depressive disorder (MDD), bipolar disorder (BPD), schizophrenia (SZ)). Whether the biological underpinnings of suicide are distinct from those of the comorbid psychiatric disorders is unclear. In our "initial study" we examined mRNA editing of 5-HT2CR in the prefrontal cortex (PFC) of persons who had suffered from BPD or SZ and died by suicide or other causes as well as in psychiatrically normal controls without suicides. We detected an increase in editing that was associated with suicide but not with the psychiatric diagnoses, demographic characteristics, psychoactive medications, alcohol or drug abuse. Based on these findings, we hypothesize that an alteration in the mRNA editing process may be one of the factors that predispose individuals toward suicidal behavior. The proposed application will investigate this phenomenon further to establish its specificity among different clinical populations and different brain regions as well as to elucidate molecular targets for future pharmacological interventions against suicidal behavior. Our initial study was focused on persons with BPD and SZ. However, given that the majority of suicides occur in persons with MDD, confidence in specificity of this phenomenon for suicidal behavior cannot be firmly established without studying 5-HT2CR editing in the context of MDD. In addition, our initial study was performed in the PFC that control decision-making and impulsivity. However, there is undoubtedly an affective component to suicide, which we will address in the proposed application by assessing editing in the amygdala and the anterior cingulate cortex. These two regions are the crucial elements of the corticolimbic circuitries that are involved in mood regulation and that are compromised in depression. In an attempt to tease out the anticipated 5-HT2CR editing changes in suicide from those that are induced by medications taken by the patients in the course of the disease, we will perform a parallel study using mice exposed to the unpredictable chronic mild stress (UCMS), which is an established model to study aspects of depression in animals. In particular, we will investigate editing alterations in UCMS-exposed mice with and without antidepressant treatment. The editing alterations (if observed) will be compared to those detected in humans with MDD and/or suicide. We will also take a first step toward elucidating the molecular mechanisms underlying the suicide- associated variations in editing. Although 5-HT2CR editing is influenced by many different factors, the most obvious explanation is an alteration in the activity of the editing enzymes (adenosine deaminases that act on RNA or ADARs). Thus, we will attempt to assess the activity of ADARs in suicide and/or MDD. PUBLIC HEALTH RELEVANCE: Despite dramatic improvements in the pharmacological treatment of psychiatric disorders associated with suicide, there has been relatively little change in suicide rates over the past 25 years. Effective pharmacological approaches toward suicidal behavior can be developed only if biological mechanisms specific for suicide are understood. According to our initial study, one of those suicide-specific mechanisms may initiate from an alteration in the mRNA editing process. The proposed application will investigate this phenomenon further, aiming to elucidate molecular targets for future pharmacological interventions against suicidal behavior.